Tacrolimus Impairment of Insulin Secretion in Isolated Rat Islets Occurs at Multiple Distal Sites in Stimulus-Secretion Coupling

Endocrinology. 2004 May;145(5):2264-72. doi: 10.1210/en.2003-1152. Epub 2004 Feb 12.

Abstract

Tacrolimus causes posttransplant diabetes mellitus, although the pathogenetic mechanisms remain controversial. We studied the mechanism of tacrolimus-induced impairment of insulin secretion using isolated rat pancreatic islets. Tacrolimus caused reductions in DNA and insulin contents per islet during 7-d culture. Tacrolimus time-dependently suppressed glucose-stimulated insulin secretion, and at a therapeutic concentration of 0.01 micromol/liter, it suppressed glucose-stimulated insulin secretion to 32 +/- 5% of the control value after 7-d incubation. Tacrolimus did not change islet glucose utilization and oxidation, ATP production, insulin mRNA expression, or the capacity for high glucose to increase intracellular Ca(2+), but altered the rapid frequency oscillations of Ca(2+) concentration. Tacrolimus suppressed insulin secretion stimulated by mitochondrial fuel (combination of l-leucine and l-glutamine, and alpha-ketoisocaproate) and glibenclamide, but not by l-arginine. Tacrolimus suppressed insulin secretion induced by carbachol and by a protein kinase C agonist in the presence or absence of extracellular Ca(2+). Under stringent Ca(2+)-free conditions, tacrolimus did not affect mastoparan-induced insulin secretion, but suppressed its glucose augmentation. Our results suggest that tacrolimus impairs glucose-stimulated insulin secretion downstream of the rise in intracellular Ca(2+) at insulin exocytosis, and that protein kinase C-mediated (Ca(2+)-dependent and independent) and Ca(2+)-independent GTP signaling pathways may be involved. However, tacrolimus-induced impaired insulin secretion was reversed 3 d after removal of the drug. Our study demonstrated that tacrolimus impairs insulin secretion at multiple steps in stimulus-secretion coupling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / analysis
  • Animals
  • Calcium / analysis
  • Calcium-Transporting ATPases / antagonists & inhibitors
  • Carbachol / pharmacology
  • Caspase 3
  • Caspases / metabolism
  • Cell Survival / drug effects
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • DNA / analysis
  • Enzyme Inhibitors / pharmacology
  • Glucose / metabolism
  • Glucose / pharmacology
  • Glyburide / pharmacology
  • Immunosuppressive Agents / adverse effects*
  • Insulin / analysis
  • Insulin / genetics
  • Insulin / metabolism*
  • Insulin Secretion
  • Intercellular Signaling Peptides and Proteins
  • Islets of Langerhans / chemistry
  • Islets of Langerhans / drug effects*
  • Islets of Langerhans / metabolism*
  • Kinetics
  • Male
  • Peptides
  • Protein Kinase C / metabolism
  • RNA, Messenger / analysis
  • Rats
  • Rats, Sprague-Dawley
  • Tacrolimus / adverse effects*
  • Thapsigargin / pharmacology
  • Wasp Venoms / pharmacology

Substances

  • Enzyme Inhibitors
  • Immunosuppressive Agents
  • Insulin
  • Intercellular Signaling Peptides and Proteins
  • Peptides
  • RNA, Messenger
  • Wasp Venoms
  • Thapsigargin
  • mastoparan
  • Adenosine Triphosphate
  • Carbachol
  • DNA
  • Cyclic AMP-Dependent Protein Kinases
  • Protein Kinase C
  • Casp3 protein, rat
  • Caspase 3
  • Caspases
  • Calcium-Transporting ATPases
  • Glucose
  • Glyburide
  • Calcium
  • Tacrolimus